(1) Field of the Invention
The present invention relates to a compound having ALXR agonist activity represented by general formula (I):
(wherein all the symbols are as defined below), a salt thereof, a solvate thereof, or a prodrug thereof (hereinafter referred to as “compound of the present invention”) and also to use thereof.
(2) Description of Related Art
ALXR (also known as: lipoxin A4 receptor, FPRL1 or FPR2) is a G-protein-coupled receptor and forms the family together with FPR1 and FPR3. It has been reported that in ALXR expression cells, the lipoxin A4 (hereinafter abbreviated as LXA4), peptide agonist, or low-molecular-weight agonist induces arachidonic acid production and intracellular Ca2+ mobilization via ALXR (Pharmacological Reviews, 2006, Vol. 58, No. 3, pp. 463-487).
LXA4 has been suggested to have anti-inflammatory and inflammation-resolution-promoting effects in various disease model animals. It is said that this inflammation-resolution-promoting effect is attributed to the promotion of the phenomenon that neutrophils that has undergone apoptosis at the location of inflammation is incorporated by macrophages via phagocytosis. It is believed that the conversion of inflammation to the resolution of inflammation is attributed to increased production of prostaglandin and also to enhanced expression of 15-lipoxygenase (hereinafter abbreviated as 15-LO), which is an LXA4 producing enzyme, at the same time. In addition, as another pathway, also in the case where the aspirin-induced acetylation of COX-2 occurs, the enzymatic catalytic activity changes, resulting in the production of epi-LXA4 or epi-LXB4.
It is expected that lipoxins and lipids of epi-lipoxins that interact with ALXR are involved in various inflammatory diseases. In particular, it has been demonstrated that forced expression of 15-LO alleviates the symptom of periodontitis. Meanwhile, the reduction of expression of LXA4 or 15-LO is correlated to the onset of ulcerative colitis or Alzheimer's disease, and LXA4 or its analogue exhibits a suppression effect on pneumonia. In addition, LXA4 or a derivative or stable analog thereof exhibits in vivo effects in disease models of dermatitis, dorsal air pouch, ischemia/reperfusion injury, peritonitis, colitis, mesangioproliferative nephritis, pleuritis, asthma, cystic fibrosis, sepsis, corneal injury, angiogenesis, periodontitis, carrageenan-induced hyperalgesia, graft-vs-host disease (GvHD), etc. (Current Opinion in Pharmacology, 2006, pp. 414-420). Further, ALXR has also been identified as a functional receptor for various peptides including prion protein fragments, human immunodeficiency virus (HIV)-1LAI strain gp120-derived peptides, and amyloid-β1-42 (Ab42) (Protein & Peptide Letters, 2007, Vol. 14, pp. 846-853), and its significant involvement in the cause of Alzheimer's disease has been suggested (FASEB Journal, 2001, Vol. 15, pp. 2454-2462).
Incidentally, the prior art relating to the compound of the present invention includes the following: a fatty acid amide hydrolase inhibitor containing a compound represented by general formula (A):
(wherein R1A represents an optionally substituted aryl or an optionally substituted heterocyclic group, R1aA represents a hydrogen atom or the like, R2A represents optionally substituted piperidine-1,4-diyl or the like, R3A represents a thiazole ring or the like, and R4A represents optionally substituted phenyl, an optionally substituted 5- or 6-membered heterocyclic group having one to four heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom, or the like (partial excerpt from the definition)) (WO 2006/054652, pamphlet); an 11β-hydroxysteroid dehydrogenase inhibitor containing a compound represented by general formula (B):
(wherein R1B and R2B represent a 6- to 10-membered saturated monocyclic or bicyclic ring formed together with a nitrogen atom to which they are attached, XB represents —C(═O)NH— or the like, and R3B represents an optionally substituted aryl, heteroaryl, or the like (partial excerpt from the definition)) (WO 2009/135581, pamphlet); and a hydroxymethylglutaryl-CoA reductase inhibitor represented by the formula:
(Journal of Combinatorial Chemistry, 2007, Vol. 9, No. 1, pp. 131-138). However, the compound of the present invention is not described, and it is not suggested that these prior art compounds have ALXR agonist activity either.